Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency

Defects in the pyruvate dehydrogenase (PDH) complex are an important cause of primary lactic acidosis, a frequent manifestation of metabolic disease i n children. Clinical symptoms can vary considerably in patients with PDH co mplex deficiencies, and almost equal numbers of affected males and females have been identified, suggesting an autosomal recessive mode of inheritance of the disease. However, the great majority of PDH complex deficiencies re sult from mutations in the X-linked pyruvate dehydrogenase (E1) alpha subun it gene (PDHA1), The major factors that contribute to the clinical variatio n in E1 alpha deficiency and its resemblance to a recessive disease are dev elopmental lethality in some males with severe mutations and the pattern of X-inactivation in females. To date, 37 different missense/nonsense and 39 different insertion/deletion mutations have been identified in the E1 alpha subunit gene of 130 patient s (61 females and 69 males) from 123 unrelated families. Insertion/deletion mutations occur preferentially in exons 10 and 11, while missense/nonsense mutations are found in all exons, In males, the majority of missense/nonse nse mutations are found in exons 3, 7, 8 and 11, and three recurrent mutati ons at codons R72, R263 and R378 account for half of these patients with mi ssense/nonsense mutations (25 of 50), A significantly lower number of femal es is found with missense/nonsense mutations (25), However, 36 females out of 55 affected patients have insertion/deletion mutations. The total number of female and male patients is thus almost the same, although a difference in the distribution of the type of mutations is evident between both sexes , In many families, the parents of the affected patients were studied for t he presence of the PDHA1 mutation. The mutation was never present in the so matic cells of the father; in 63 mothers studied, 16 were carriers (25%), I n four families, the origin of the new mutation was determined to be twice paternal and twice maternal, Hum Mutat 15:209-219, 2000, (C) 2000 Wiley-Lis s, Inc.